Lung Transplant Unit, St Vincent's Hospital Darlinghurst, Sydney, Australia.
UNSW Medicine, St Vincent's Hospital Clinical School, Sydney, Australia.
Eur J Clin Pharmacol. 2019 Jul;75(7):879-888. doi: 10.1007/s00228-019-02658-5. Epub 2019 Mar 12.
To (i) describe tacrolimus (TAC) pre-dose concentrations (C), (ii) calculate apparent oral TAC clearance (CL/F) adjusted for measured haematocrit (HCTi) and standardised to a HCT of 45%, across three observation time points and (iii) explore if low TAC C or high mean CL/F are associated with an increased risk of rejection episodes early after lung transplantation.
TAC whole blood concentration-time profiles and transbronchial biopsies were performed prospectively at weeks 3, 6 and 12 after lung transplantation. The TAC pre-dose concentration (C) was measured, and CL/F was determined using non-compartmental analysis. The associations between TAC C and CL/F and rejection status were explored using repeated measures logistic regression.
Eighteen patients provided 377 TAC whole blood concentrations. Considerable variability around the median (IQR) CL/F 6.8 (4.2-15.9) L h, and the median C 12.7 (9.9-16.6) μg L was noted. Despite adjustment for haematocrit, a significant decrease was observed in CL/F in all patients over time: CL/F 14 (5.4-23) at week 3, CL/F 7.7 (4.5-12) at week 6 and CL/F 3.9 (2.4-11) L h at week 12 (p < 0.01). Seven (38.9%) patients experienced a single grade 2 rejection, whilst 11 (61.1%) patients experienced no rejection. Higher TAC C were associated with a reduced risk of rejection OR 0.68 (95% CI 0.51-0.91, p = 0.02), and greater mean CL/F was associated with an increased risk of rejection OR 1.34 (95% CI 1.01-1.81 p = 0.04).
Monitoring TAC C, HCT and CL/F in patients after lung transplantation may assist clinicians in detecting patients at risk of acute rejection and may guide future research into TAC and HCT monitoring after lung transplantation.
（i）描述他克莫司（TAC）的预剂量浓度（C），（ii）计算调整为测量的红细胞压积（HCTi）并标准化为 45%的HCT的表观口服 TAC 清除率（CL/F），跨越三个观察时间点，（iii）探讨低 TAC C 或高平均 CL/F 是否与肺移植后早期排斥反应的风险增加有关。
在肺移植后 3、6 和 12 周进行前瞻性的 TAC 全血浓度-时间曲线和经支气管活检。测量 TAC 预剂量浓度（C），并使用非房室分析确定 CL/F。使用重复测量逻辑回归探讨 TAC C 和 CL/F 与排斥状态之间的关联。
18 名患者提供了 377 个 TAC 全血浓度。中位（IQR）CL/F 6.8（4.2-15.9）L/h 和中位 C 12.7（9.9-16.6）μg/L 周围存在相当大的变异性。尽管调整了红细胞压积，但所有患者的 CL/F 在时间上均显著下降：第 3 周时 CL/F 为 14（5.4-23），第 6 周时 CL/F 为 7.7（4.5-12），第 12 周时 CL/F 为 3.9（2.4-11）L/h（p<0.01）。7（38.9%）名患者发生了 1 次 2 级排斥反应，而 11（61.1%）名患者未发生排斥反应。较高的 TAC C 与排斥反应的风险降低相关，OR 0.68（95%CI 0.51-0.91，p=0.02），平均 CL/F 较高与排斥反应的风险增加相关，OR 1.34（95%CI 1.01-1.81，p=0.04）。
监测肺移植后患者的 TAC C、HCT 和 CL/F 可能有助于临床医生检测有急性排斥反应风险的患者，并可能指导未来关于肺移植后 TAC 和 HCT 监测的研究。
